CN110801434A - A method for preparing lapatinib tosylate solid dispersion by freeze-drying method - Google Patents

Abstract

The invention discloses a method for preparing lapatinib tosylate solid dispersion by freeze-drying method. The physical mixture (containing Lapatinib ditosylate) was added to the acetonitrile solution, ultrasonicated to make it completely dissolved, the solution was quickly frozen in liquid nitrogen, dried in a freeze dryer for 24-36h, taken out and placed in a P ₂ O ₅ desiccator for 24- For 48h, pass through a 60-100 mesh sieve for later use to prepare lapatinib tosylate solid dispersion. The solubility in water and the dissolution rate of the solid dispersion of lapatinib tosylate prepared by the method of the invention are improved, and the bioavailability of the product is improved.

Description

A method for preparing lapatinib tosylate solid dispersion by freeze-drying method

technical field

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a method for preparing a solid dispersion of lapatinib tosylate by a freeze-drying method.

Background technique

Lapatinib tosylate belongs to the TKI (Tyrosine Kinase Inhibitor) class of drugs that binds reversibly to human epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (Her2) tyrosine via hydrogen bonding At the ATP binding site of the kinase, it prevents ArIP from binding to the tyrosine kinase domain and inhibits the autophosphorylation and activation of the tyrosine kinase. Lapatinib tosylate also inhibits the activation of MAPK, the downstream effector of EGFR and Her2, thereby inhibiting tumor cell proliferation. In addition, lapatinib tosylate inhibits Akt activation, leading to tumor cell apoptosis, for the treatment of advanced or metastatic breast cancer.

Lapatinib tosylate was developed by GlaxoSmithKline and was first approved in the United States in March 2007. In 2013, my country imported lapatinib tosylate tablets (0.25g/tablet) produced in the United Kingdom. Packaged sales. The patent protection of the drug will expire in June 2021, when a large number of drug manufacturers will apply for 3+6 new drugs.

The bioavailability of lapatinib tosylate is low, and the bioavailability in animal tests is only 10-20%. It relies on high-dose administration to achieve curative effect, and needs to be administered 1250mg per day; taking it with food can increase absorption, and taking it with food is low-fat. On food (5% fat-500 calories) and high-fat food (50% fat-1000 calories), AUC values increased 3-fold and 4-fold, and _Cmax increased 2.5-fold and 3-fold, respectively.

Lapatinib tosylate has incomplete absorption in the gastrointestinal tract, large individual differences, low bioavailability, and is easily affected by many factors such as diet and gastric emptying. Therefore, based on the application technology research to improve the bioavailability of lapatinib tosylate, it is a subject worthy of in-depth research by researchers.

The solubility of lapatinib tosylate in water is 0.007mg/ml, and in 0.1mol/L hydrochloric acid: 0.001mg/ml, low solubility is the main reason for its low bioavailability. Solubilization methods for poorly soluble drugs mainly include micronization, surfactant micelle solubilization, cosolvent solubilization, β-cyclodextrin inclusion complex solubilization, microemulsion solubilization, solid dispersion solubilization and preparation of water-soluble complexes, etc. Yuan Duanfeng from West China University in Sichuan, China, etc. have reported the preparation and characterization of lapatinib albumin nanoparticles freeze-dried powder injection, but did not report the effect of improving bioavailability. There is still no effective solution on how to increase the solubility of lapatinib tosylate to improve bioavailability.

In order to solve the problem of low bioavailability of toluenesulfonic acid, the project team investigated micronization and solubilization of surfactants in the early stage, and the results showed that the effects were not ideal. The solid dispersion (SD) prepared by using polyethylene glycol 1000 vitamin E succinate (TPGS) as the carrier has a certain solubilization effect. Preliminary research provides ideas for carrying out this project.

Lapatinib ditosylate belongs to the class of small molecule targeted tyrosine kinase inhibitors and is the world's first marketed drug targeting human epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2. (HER2)-positive breast cancer oral drug, clinically used for the treatment of advanced or metastatic breast cancer patients with HER2 overexpression and previous treatment including anthracyclines, purines, and trastuzumab.

At present, there is a lack of a method for preparing lapatinib tosylate solid dispersion by freeze-drying method with high bioavailability.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a method for preparing lapatinib tosylate solid dispersion by freeze-drying method.

The technical scheme of the present invention is as follows: a method for preparing lapatinib tosylate solid dispersion by a freeze-drying method of the present invention includes the following steps: (1) combining the polymer carrier PVPS630 with the raw material lapatinib tosylate , prepare the physical mixture according to the proportion; (2) take the physical mixture (containing Lapatinib ditosylate, lapatinib tosylate), add it to the acetonitrile solution, ultrasonicate it to make it completely dissolved, the solution is placed in liquid nitrogen and quickly frozen, placed in the freezer Dry in a desiccator for 24-36 h, take out and place in a P ₂ O ₅ desiccator for 24-48 h, pass through a 60-100 mesh sieve for later use, and prepare a solid dispersion of lapatinib tosylate.

Further, in step (1), the drug loading ratio is 1:1-1:3.

Further, in step (2), the weight volume ratio of the physical mixture to the acetonitrile solution is 500 mg: 30-100 mL.

Further, in step (2), the volume ratio of acetonitrile in the acetonitrile solution is 50%-100%.

Further, in step (2), the temperature in the freeze dryer is -40°C, and the temperature of the cold well is -60°C.

Beneficial effects: the solubility and dissolution rate of lapatinib tosylate solid dispersion in water prepared by the method of the present invention are improved, and the bioavailability of the product is improved.

Compared with the prior art, the present invention has the following advantages: (1) the freeze-drying technology of the present invention inhibits the growth of the crystal nucleus of the raw material during the preparation process, and the product is loosely packed and has a large surface area, which is conducive to the dissolution and dissolution of the raw material, Widely used in the preparation of solid dispersions. In this study, freeze-drying technology was used to prepare lapatinib tosylate solid dispersion to improve its solubility and dissolution, thereby achieving the purpose of improving bioavailability.

组。DSC、XRPT、SEM等表征结果显示，PVPS630为载体的固体分散体中，原料均以非晶态存在，而以

为载体时，只有药载比为1:3条件下，原料才呈现非晶态特征。大鼠药动学测定结果表明固体分散体(Lapatinib ditosylate:PVPS630 1:3)较上市药品AUC(药时曲线下面积)提高23.64％。结论载体PVPS630与甲苯磺酸拉帕替尼的相容性更理想；固体分散技术有助于本品提高生物利用度。(2) The present invention prepares lapatinib tosylate solid dispersion (solid dispersion, SD) to improve its bioavailability. Methods Using PVPS630 (copovidone S630) as the carrier, the solid dispersion of lapatinib tosylate was prepared by freeze-drying method. The solid dispersion was characterized by means of ray powder diffraction), and the solubilization effect and the improvement of bioavailability of the solid dispersion were evaluated by the determination of apparent solubility, dissolution and pharmacokinetics in rats. Results Under the same drug loading ratio, the dissolution and apparent solubility of PVPS630 group were better than those of PVPS630 group.

Group. The characterization results of DSC, XRPT and SEM show that in the solid dispersion with PVPS630 as the carrier, the raw materials exist in an amorphous state, while the raw materials are in an amorphous state.

When it is used as a carrier, only under the condition that the drug loading ratio is 1:3, the raw material exhibits amorphous characteristics. The results of pharmacokinetic assay in rats showed that the AUC (area under the curve) of the solid dispersion (Lapatinib ditosylate:PVPS630 1:3) was increased by 23.64% compared with the listed drug. Conclusion The compatibility between the carrier PVPS630 and lapatinib tosylate is more ideal; the solid dispersion technology can help this product to improve the bioavailability.

Description of drawings

为载体的样品DSC检测图。Fig. 1 is the basis of the present invention

The sample DSC detection chart of the carrier.

Fig. 2 is the sample DSC detection diagram of the present invention taking PVPS630 as carrier;

为载体的样品XRPD检测图；Fig. 3 is the base of the present invention

The sample XRPD detection chart of the carrier;

Fig. 4 is the sample XRPD detection figure that takes PVPS630 as carrier of the present invention;

为载体的SD SEM检测结果(2000×～5000×)图。Fig. 5 is the base of the present invention

It is the SD SEM detection result (2000×～5000×) of the carrier.

FIG. 6 is a graph of the SD SEM detection results (2000×～5000×) using PVPS630 as a carrier of the present invention.

为载体各样品溶出度检测结果图。Fig. 7 is the base of the present invention

It is a graph of the dissolution test results of each sample of the carrier.

Figure 8 shows the results of the dissolution test of each sample of the carrier for PVPS630 of the present invention.

Fig. 9 is a single-dose administration plasma concentration-time curve diagram of the present invention.

Detailed ways

The present invention is further illustrated by the following examples. It should be understood that these embodiments are illustrative and exemplifying of the present invention and do not limit the scope of the present invention in any way.

Example 1

A method for preparing lapatinib tosylate solid dispersion by a freeze-drying method of the present invention includes the following steps: (1) using the carrier PVPS630 as a polymer material, and preparing a physical mixture with a drug loading ratio; The ratio is 1:1. (2) Take the physical mixture (containing Lapatinib ditosylate), add it to 30 mL of acetonitrile solution, ultrasonicate to make it completely dissolved, put the solution in liquid nitrogen and freeze it quickly, put it in a freeze dryer to dry for 30 hours, and take it out and put it in a P ₂ O ₅ desiccator For 30h, pass through a 60-mesh sieve for later use to prepare lapatinib tosylate solid dispersion. The weight-volume ratio of the physical mixture to the acetonitrile solution was 500 mg: 30 mL. The volume ratio of acetonitrile to water in the acetonitrile solution is 2:1. The temperature in the freeze dryer is -40°C, and the temperature of the cold well is -60°C.

Example 2

The difference between Example 2 and Example 1 is that: a method for preparing lapatinib tosylate solid dispersion by a freeze-drying method of the present invention includes the following steps: (1) using the carrier PVPS630 as a polymer material, and carrying out the drug treatment. The physical mixture is prepared at the loading ratio; the drug loading ratio is 1:3. (2) Take the physical mixture (containing Lapatinib ditosylate), add it to 30 mL of acetonitrile solution, make it completely dissolved by ultrasound, put the solution in liquid nitrogen and freeze it quickly, put it in a freeze dryer to dry for ₂₄ hours, and take it out and put it in a _P2O5 dryer For 24 hours, pass through a 100-mesh sieve for later use to prepare lapatinib tosylate solid dispersion. The weight-volume ratio of the physical mixture to the acetonitrile solution is 500 mg: 100 mL. The volume ratio of acetonitrile to water in the acetonitrile solution is 2:1. The temperature in the freeze dryer is -40°C, and the temperature of the cold well is -60°C.

Example 3

The difference between Example 3 and Example 1 is: a method for preparing lapatinib tosylate solid dispersion by a freeze-drying method of the present invention includes the following steps: (1) using the carrier PVPS630 as a polymer material, and carrying out the drug treatment. The physical mixture is formulated with the loading ratio; the drug loading ratio is 1:2. (2) Take the physical mixture (containing Lapatinib ditosylate), add it to 30 mL of acetonitrile solution, ultrasonicate it to make it completely dissolved, put the solution in liquid nitrogen and freeze it quickly, put it in a freeze dryer to dry for 36 _hours , and take it out and put it in a _P2O5 dryer For 48 hours, pass through an 80-mesh sieve for later use to prepare lapatinib tosylate solid dispersion. The weight-volume ratio of the physical mixture to the acetonitrile solution is 500 mg: 60 mL. The volume ratio of acetonitrile to water in the acetonitrile solution is 2:1. The temperature in the freeze dryer is -40°C, and the temperature of the cold well is -60°C.

Experimental example 1

1 Instruments, reagents and animals

1.1 Instruments and Reagents

(德国BASF，批号：84414368E0)，PVPS630(上海德祥医药科技有限公司，批号：DX1608250235)，甲苯磺酸拉帕替尼对照片(

GSK，批号：17045073)，乙腈、醋酸胺、冰醋酸等均为分析纯。Raw material of lapatinib tosylate (Yangzhou Qinyuan Pharmaceutical Technology Co., Ltd., batch number: 170904, content 99.73%),

(BASF, Germany, batch number: 84414368E0), PVPS630 (Shanghai Dexiang Pharmaceutical Technology Co., Ltd., batch number: DX1608250235), lapatinib tosylate on the photo (

GSK, batch number: 17045073), acetonitrile, amine acetate, glacial acetic acid, etc. were all analytically pure.

Netzsch STA-449F5 differential scanning calorimeter (Germany); X'Pert Powder X-ray diffractometer (Netherlands); supra 55 scanning electron microscope (Germany); RCZ-6C3 intelligent dissolution apparatus (Tianjin Tianda); Agilent1200 high-efficiency liquid Phase chromatograph (Agilent, USA).

1.2 Experimental animals

12 Sprague-Dawley rats, all male, weighing 200±20g, provided by Zhejiang Weitong Lihua Laboratory Animal Co., Ltd., license number: SCXK (Zhe) 2018-0001, raised in Zhejiang Institute of Traditional Chinese Medicine Center, license number: SYXK (Zhe 2014-0003).

2 Methods and results

2.1 Determination of Lapatinib Tosylate

2.1.1 Chromatographic conditions: use an Agilent C18 (4.6mm×250mm, 5mm) chromatographic column; use ammonium acetate buffer (take 3.0 g of ammonium acetate, add 1 L of water to dissolve, and adjust to pH 4.0 with glacial acetic acid): acetonitrile 1: 1 is the mobile phase, the flow rate is 1 mL/min; the column temperature is 40 °C, the detection wavelength is 260 nm, and the injection volume is 10 μL ^[8] .

2.1.2 Determination method of sample content: take the sample, grind it in a mortar, accurately weigh an appropriate amount (about 10 mg of Lapatinib), put it in a 25 mL volumetric flask, add an appropriate amount of mobile phase, dissolve it by ultrasonic, and add mobile phase to volume, namely get the sample solution. Another appropriate amount of the reference substance of lapatinib tosylate was taken, and the mobile phase was added to make a reference substance solution containing 0.4 mg/mL of lapatinib, which was determined by the external standard method.

2.2 Solubilization of the drug by the carrier

PVPS630为高分子材料，均具有表面活性，对拉帕替尼具有一定的胶束增溶作用。按表1配制不同比例的物理混合物，称取适量(约相当于Lapatinib 40mg)，置25mL容量瓶中，加水20mL，超声20min，定容，置室温2h，按2.1.1色谱条件测定。各样品的载体对原料的增溶效果的表观溶解度结果见表1：carrier

PVPS630 is a polymer material with surface activity, which has a certain micellar solubilization effect on lapatinib. Prepare physical mixtures in different proportions according to Table 1, weigh an appropriate amount (approximately equivalent to 40mg of Lapatinib), put it in a 25mL volumetric flask, add 20mL of water, ultrasonicate for 20min, set the volume, set it to room temperature for 2h, and measure it according to the chromatographic conditions of 2.1.1. The apparent solubility results of the solubilization effect of the carrier of each sample on the raw materials are shown in Table 1:

Table 1

的增溶效果优于PVPS630。It can be seen from the test results that under the same drug loading ratio conditions,

The solubilization effect is better than that of PVPS630.

2.3 Preparation of solid dispersions

The physical mixture prepared according to the drug loading ratio in Table 1, take the mixture (containing 500 mg of Lapatinib ditosylate), add it to 30 mL of acetonitrile solution (acetonitrile: water 2:1), ultrasonically make it completely dissolved, and the solution is placed in liquid nitrogen and quickly frozen , put it in a freeze dryer (-40°C, cold well -60°C) to dry for 48h, take it out and put it in a _P2O5 dryer for 24h, pass it through an 80 _- mesh sieve for use.

2.4 Determination of apparent solubility of solid dispersions

The prepared solid dispersion was prepared according to the method under item 2.2, and the apparent solubility was measured according to the chromatographic conditions of 2.1.1, and the solubilization effect was compared. The results are shown in Table 2. The apparent solubility measurement of the solid dispersion is shown in Table 2:

Table 2

和54.27倍(PVPS630)。这可能是因为药物在固体分散体中以微晶、无定形等状态存在，且由于亲水性载体增加了药物的可润湿性，在溶液中快速形成了过饱和溶液，同时由于溶液中高分子载体的抑晶作用，阻滞了药物的结晶析出，维持溶液处于过饱和状态。It can be seen from the test results that the prepared solid dispersion can significantly increase the apparent solubility of this product, while the solubilization effect of polymer micelles is basically negligible. Under the conditions of the same drug loading ratio, the solubilization effect of PVPS630 on the raw materials is more significant. Under the condition that the drug loading ratio is 1:3, the apparent solubility of the two groups of solid dispersions is 32.04 times that of the raw materials, respectively.

and 54.27 times (PVPS630). This may be because the drug exists in the state of microcrystalline, amorphous, etc. in the solid dispersion, and because the hydrophilic carrier increases the wettability of the drug, a supersaturated solution is rapidly formed in the solution. The crystal inhibitory effect of the carrier blocks the crystallization of the drug and keeps the solution in a supersaturated state.

2.5 Differential Scanning Calorimetry (DSC)

物理混合物、固体分散体进行检测，结果见图1-图2。图1中，physical mixture--物理混合物，1:3SD---1:3固体分散体，1:2SD--1:2固体分散体，1:1SD---1:1固体分散体，HEAT FLOW热参数，temperture温度，lapatinib拉帕替尼，ditosylate甲苯磺酸。Take an empty aluminum crucible as a reference, the atmosphere is nitrogen, the heating rate is 10°C·min ^-1 , and the scan is performed in the range of 30-300°C. Take lapatinib tosylate raw material, PVPS630,

Physical mixtures and solid dispersions were tested, and the results are shown in Figures 1-2. In Figure 1, physical mixture--physical mixture, 1:3SD---1:3 solid dispersion, 1:2SD--1:2 solid dispersion, 1:1SD---1:1 solid dispersion, HEAT FLOW thermal parameters, temperature temperature, lapatinib, ditosylate tosylate.

为载体的固体分散体中，当药载比为1:1和1:2时，仍有明显的原料晶体熔点峰，但当药载比为1:3时，原料晶体熔点峰已消失。而以PVPS630为载体的固体分散体中，各药载条件下均无明显的原料晶体熔点峰，表明甲苯磺酸拉帕替尼在固体分散体中呈非晶态分布。The results show that the melting point of the raw material is around 251°C. by

In the solid dispersion as the carrier, when the drug loading ratio is 1:1 and 1:2, there is still an obvious melting point peak of the raw material crystal, but when the drug loading ratio is 1:3, the melting point peak of the raw material crystal has disappeared. In the solid dispersion with PVPS630 as the carrier, there is no obvious melting point peak of raw material crystal under each drug loading condition, indicating that lapatinib tosylate is amorphous in the solid dispersion.

2.6 X-ray powder diffraction (XRPD)

The measurement conditions are: tube current 40mA, tube voltage 40kV, starting angle 3.0°, ending angle 90°, scanning speed 12°/min, step size 0.02°. XRPD analysis was performed on the API, carrier, physical mixture, and solid dispersion, respectively, and the results are shown in Figure 3-4. Figure 4. The XRPD detection diagram of the sample with PVPS630 as the carrier.

为载体的物理混合物中，相应的位置均有特征峰，但由于载体的稀释作用，峰的强度减弱。It can be seen from the XRPD pattern that lapatinib tosylate crystals have characteristic peaks at 6.7°, 8.4°, 11.5°, 12.1°, 18.1°, 21.2°, 24°, etc. ^[12] .

In the physical mixture of the carrier, there are characteristic peaks at the corresponding positions, but the intensity of the peaks is weakened due to the dilution of the carrier.

为载体制备的固体分散体中，当药载比为1:1和1:2时，固体分散体在8°左右仍出现有微弱的晶体峰，表明原料仍有部分呈微晶状态；当药载比为1:3时，已无晶体峰出现，表明原料呈非晶态分布。以PVPS630为载体制备的固体分散体中，各药载比条件下甲苯磺酸拉帕替尼的晶体峰均不明显，表明原料呈无定形态存在。XRPD检测结果与DSC检测结果基本一致。by

In the solid dispersion prepared as a carrier, when the drug loading ratio is 1:1 and 1:2, the solid dispersion still has a weak crystal peak at about 8°, indicating that the raw material is still partially in a microcrystalline state; When the loading ratio was 1:3, no crystal peak appeared, indicating that the raw material was distributed in an amorphous state. In the solid dispersion prepared with PVPS630 as the carrier, the crystal peaks of lapatinib tosylate were not obvious under the conditions of various drug loading ratios, indicating that the raw materials existed in an amorphous state. The XRPD detection results were basically consistent with the DSC detection results.

2.7 Scanning Electron Microscopy (SEM)

为载体的SD SEM检测结果(2000×～5000×)；The raw material, carrier, physical mixture and solid dispersion were treated with gold spray for 3 minutes to improve their conductivity, and then observed under electron microscope. The results are shown in Figure 5-6. Figure 5 to

is the SD SEM test result of the carrier (2000×～5000×);

C-物理混合物(原料:

1:3)；D-SD(原料:

1:1)；E-SD(原料:1:2)；F-SD(原料:

1:3)。图6以PVPS630为载体的SD SEM检测结果(2000×～5000×)；A-甲苯磺酸拉帕替尼；G-PVPS630；H-物理混合物(原料:PVPS630 1:3)；I-SD(原料:PVPS630 1:1)；J-SD(原料:PVPS630 1:2)；K-SD(原料:PVPS630 1:3)。A-lapatinib tosylate;

C-Physical Mixture (Ingredients:

1:3); D-SD (raw material:

1:1); E-SD (raw material: 1:2); F-SD (raw material:

1:3). Figure 6 SD SEM detection results with PVPS630 as carrier (2000×～5000×); A-lapatinib tosylate; G-PVPS630; H-physical mixture (raw material: PVPS630 1:3); I-SD ( Raw material: PVPS630 1:1); J-SD (raw material: PVPS630 1:2); K-SD (raw material: PVPS630 1:3).

为块状晶体，PVPS630呈球状，物理混合物中可明显看出原料粘附在

和PVPS630表面。在

为载体的固体分散体中，当药载比为1:1时，原料晶态明显；药载比为1:2时，仍能看到少量柱状晶体原料；药载比为1:3时已基本看不到原料的晶体。以PVPS630为载体的固体分散体中，在各药载比条件下SEM中均看不到原料晶体存在。SEM结果与DSC和XRPD结果一致。It can be seen from the SEM image that lapatinib tosylate is in the form of needle or columnar crystals.

It is a block crystal, PVPS630 is spherical, and it is obvious from the physical mixture that the raw material adheres to the

and PVPS630 surface. exist

In the solid dispersion as the carrier, when the drug loading ratio is 1:1, the crystalline state of the raw materials is obvious; when the drug loading ratio is 1:2, a small amount of columnar crystal raw materials can still be seen; when the drug loading ratio is 1:3, the The crystals of the raw material were hardly seen. In the solid dispersion with PVPS630 as the carrier, no raw crystals can be seen in the SEM under the conditions of various drug loading ratios. The SEM results are consistent with the DSC and XRPD results.

2.8 Dissolution determination

溶出度测定方法，采用浆法(铁丝网固定)，以2％吐温盐酸溶液(0.1N)900mL为溶出介质(漏槽浓度为：0.4296mg/mL)，转速为55r，分别于5、10、15、20、30、45、60min取样5mL，0.45μm滤膜滤过，及时补充新鲜的溶出介质。按2.1.1色谱条件测定。溶出结果见图7-8。图7为本发明的以

为载体各样品溶出度检测结果图。图8为本发明的PVPS630为载体各样品溶出度检测结果图。Take an appropriate amount of lapatinib raw material, physical mixture, and prepared solid dispersion (containing 125 mg of Lapatinib), put it in a capsule, and refer to the FDA announced

The dissolution determination method adopts the slurry method (fixed by wire mesh), 900 mL of 2% Tween hydrochloric acid solution (0.1N) is used as the dissolution medium (sink concentration: 0.4296 mg/mL), and the rotation speed is 55r, respectively. 15, 20, 30, 45, 60min sampling 5mL, 0.45μm filter membrane filtration, timely replenishment of fresh dissolution medium. Determine according to 2.1.1 chromatographic conditions. The dissolution results are shown in Figures 7-8. Fig. 7 is the base of the present invention

It is a graph of the dissolution test results of each sample of the carrier. FIG. 8 is a graph showing the results of the dissolution test of each sample of PVPS630 of the present invention as a carrier.

对原料的增溶效果要优于PVPS630，可能是因为其表面活性作用较强所致；但固体分散体的溶出度测定中，在相同药载比的条件下，PVPS630的增溶效果更理想，在药载比大于2时，60分钟基本释放完全。in physical mixture

The solubilization effect of raw materials is better than that of PVPS630, which may be due to its strong surface activity; but in the dissolution determination of solid dispersions, under the conditions of the same drug loading ratio, the solubilization effect of PVPS630 is more ideal. When the drug loading ratio is greater than 2, the release is basically complete in 60 minutes.

2.9 Pharmacokinetic study in rats

和固体分散体(Lapatinib ditosylate:PVPS630 1:3)混悬液，剂量均为650mg/kg(以Lapatinib计)，给药后0、10min、25min、40min、1h、2h、3h、4h、6h、8h、12h、18h和24h从大鼠眼眶静脉丛采血250μL，将血样置于肝素抗凝的具塞离心管中，4000r·min^-1离心10min，分离血浆，精密吸取0.1mL血浆，加入0.2mL乙腈，沉淀蛋白，13000r·min^-1离心10min，取上清液按2.1.1色谱条件测定拉帕替尼含量，样品进样量为20μL，标准品进样量为4μL。测定的平均药时曲线见图9。图9单剂量给药血药浓度-时间曲线图。采用DAS 3.0软件计算药动学参数，固体分散体和对照药大鼠药动学参数(n＝6)的结果如表3所示。Twelve Sprague-Dawley rats, all male, were randomly divided into two groups after 1 week of adaptive feeding, and were given the marketed control drug respectively.

and solid dispersion (Lapatinib ditosylate:PVPS630 1:3) suspension, the dose is 650mg/kg (calculated as Lapatinib), 0, 10min, 25min, 40min, 1h, 2h, 3h, 4h, 6h, At 8h, 12h, 18h and 24h, 250 μL of blood was collected from the orbital venous plexus of the rat, and the blood sample was placed in a heparin anticoagulated centrifuge tube with a stopper, centrifuged at 4000r·min ^-1 for 10min, and the plasma was separated. Acetonitrile was used to precipitate proteins, centrifuged at 13,000 r·min ^-1 for 10 min, and the supernatant was taken to determine the lapatinib content according to the chromatographic conditions in 2.1.1. The sample injection volume was 20 μL, and the standard sample injection volume was 4 μL. The measured mean drug-time curve is shown in Figure 9. Figure 9. Single-dose administration plasma concentration-time profile. DAS 3.0 software was used to calculate the pharmacokinetic parameters, and the results of the pharmacokinetic parameters of the solid dispersion and the control drug in rats (n=6) are shown in Table 3.

table 3

Note: * means P<0.05 compared with the listed drugs.

3 Discussion

两种高分子载体的增溶效果进行了对比研究。结果表明，在相同药载比的条件下，PVPS630为载体制备的固体分散体溶出度和表观溶解度均明显优于

组。DSC、XRAY、SEM等表征结果也显示，各载药比条件下，PVPS630为载体的各固体分散体组中原料均以非晶态存在，而以

为载体的固体分散体组中，只有在药载比为1:3时才呈现非晶态特征，表明PVPS630与原料的相容性更理想。Lapatinib tosylate is a BCS class IV drug. The solubility and permeability of the drug are both rate-limiting factors for drug absorption. This study investigated the effect of increasing the apparent solubility and dissolution rate of the drug on absorption. The research used freeze-drying technology to prepare solid dispersion, and the PVPS630 and

The solubilization effects of the two polymer carriers were compared. The results showed that under the same drug loading ratio, the dissolution and apparent solubility of the solid dispersion prepared with PVPS630 as the carrier were significantly better than those of the solid dispersion.

Group. The characterization results of DSC, XRAY and SEM also showed that under the conditions of various drug loading ratios, the raw materials in each solid dispersion group with PVPS630 as the carrier existed in an amorphous state, while the

In the solid dispersion group as the carrier, only when the drug loading ratio is 1:3, the amorphous character is presented, indicating that the compatibility of PVPS630 with the raw materials is more ideal.

For solid dispersion (Lapatinib ditosylate:PVPS630 1:3) and marketed drugs The pharmacokinetics of single-dose oral administration in rats was compared, and the results showed that the peak concentration of the solid dispersion group was higher, reaching 27.50 ± 5.30 μg/mL, and the area under the curve of the drug was increased by 23.64% compared with the marketed sample, and was comparable to the marketed drug. comparison is statistically significant. The results of the study showed that solid dispersion technology could help to improve the bioavailability of lapatinib tosylate.

为载体，采用冷冻干燥法制备甲苯磺酸拉帕替尼固体分散体，通过SEM、DSC、XRPT等手段对固体分散体进行表征，通过表观溶解度、溶出度和大鼠体内药动学测定，评价固体分散体的增溶效果和生物利用度的改善情况。结果在相同药载比的条件下，PVPS630组的溶出度和表观溶解度均优于组。DSC、XRPT、SEM等表征结果显示，PVPS630为载体的固体分散体中，原料均以非晶态存在，而以

为载体时，只有药载比为1:3条件下，原料才呈现非晶态特征。大鼠药动学测定结果表明固体分散体(Lapatinib ditosylate:PVPS630 1:3)较上市药品AUC提高23.64％。结论为载体PVPS630与甲苯磺酸拉帕替尼的相容性更理想；固体分散技术有助于本品提高生物利用度。The present invention prepares lapatinib tosylate solid dispersion (solid dispersion, SD) to improve its bioavailability. method to PVPS630 and

As the carrier, the solid dispersion of lapatinib tosylate was prepared by freeze-drying method. The solid dispersion was characterized by SEM, DSC, XRPT and other means, and the apparent solubility, dissolution and pharmacokinetics in rats were determined. The solubilization effect and bioavailability improvement of solid dispersions were evaluated. Results Under the same drug loading ratio, the dissolution and apparent solubility of PVPS630 group were better than those of PVPS630 group. Group. The characterization results of DSC, XRPT and SEM show that in the solid dispersion with PVPS630 as the carrier, the raw materials exist in an amorphous state, while the raw materials are in an amorphous state.

When it is used as a carrier, only under the condition that the drug loading ratio is 1:3, the raw material exhibits amorphous characteristics. The results of pharmacokinetic assay in rats showed that the AUC of the solid dispersion (Lapatinib ditosylate:PVPS630 1:3) was 23.64% higher than that of the listed drug. The conclusion is that the compatibility between the carrier PVPS630 and lapatinib tosylate is more ideal; the solid dispersion technology can help this product to improve the bioavailability.

The specific embodiments described herein are merely illustrative of the spirit of the invention. Those skilled in the art to which the present invention pertains can make various modifications or additions to the described specific embodiments or substitute in similar manners, but will not deviate from the spirit of the present invention or go beyond the definitions of the appended claims range.

Claims (5)

1. A method for preparing lapatinib tosylate solid dispersion by a freeze-drying method is characterized by comprising the following steps:

(1) preparing physical mixtures with different drug loading ratios by taking high molecular material PVPS630 copovidone S630 as a carrier;

(2) taking a physical mixture containing Lapatinib ditosylate and Lapatinib tosylate, adding the physical mixture into an acetonitrile solution, carrying out ultrasonic treatment to completely dissolve the physical mixture, quickly freezing the solution in liquid nitrogen, drying the solution in a freeze-drying drier for 24 to 36 hours, taking out the solution and placing the solution in a freeze-drying drier for 24 to 36 hours, and taking out the solution and placing the solution in a container P₂O₅And (4) sieving the mixture for 24-48h in a dryer by using a 60-100 mesh sieve for later use to prepare the lapatinib tosylate solid dispersion.

2. The lyophilization process for preparing lapatinib tosylate solid dispersion according to claim 1, characterized in that: in the step (1), the drug loading ratio is 1:1-1: 3.

3. The lyophilization process for preparing lapatinib tosylate solid dispersion according to claim 1, characterized in that: in the step (2), the weight-to-volume ratio of the physical mixture to the acetonitrile solution is 500 mg: 30-100 mL.

4. The lyophilization process for preparing lapatinib tosylate solid dispersion according to claim 1, characterized in that: in the step (2), the volume ratio of the acetonitrile in the acetonitrile solution is 50-100%.

5. The lyophilization process for preparing lapatinib tosylate solid dispersion according to claim 1, characterized in that: in the step (2), the temperature in the freeze dryer is-40 ℃, and the temperature of the cold well is-60 ℃.

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